Predicting and Confirming Bioequivalence of Alpelisib Oral Granules and Tablets for Patients With PIK3CA-Related...

Alpelisib, an oral α-specific phosphoinositide 3-kinase (PI3K) inhibitor, has been shown to be safe and effective for some patients with gain-of-function mutation in the PIK3CA oncogene. Alpelisib has received US FDA accelerated approval as Vijoice® film-coated tablets to treat severe PIK3CA-Related Overgrowth Spectrum (PROS). PROS typically displays clinical manifestations in the first year of patient life. Therefore, oral granules were developed as an age-appropriate pediatric dosage form. Bioequivalence between alpelisib granules and tablet and the effect of food on granules pharmacokinetics were assessed in a single-center, randomized, three-treatment, six-sequence, three-period, crossover study among 60 healthy adults. Participants were randomly assigned to receive a single 50-mg alpelisib dose as: (i) tablet following a meal, (ii) granules following a meal, and (iii) granules while fasting. Statistical analysis of non-compartmental pharmacokinetic parameters demonstrated bioequivalence between the 50-mg alpelisib granules and tablet forms when administered with food: estimated geometric mean ratios (90% confidence interval) for granules-versus-tablet area under the curve (AUC) from time zero to infinity (AUC_inf), to the last measurable concentration (AUC_last) and maximum observed concentration (C_max) were 0.984 (0.952, 1.02), 0.980 (0.946, 1.02), and 0.947 (0.891, 1.01), respectively. No clinically relevant food effect on 50-mg alpelisib granules pharmacokinetics was observed. These results were accurately predicted using physiologically based biopharmaceutical modeling. Alpelisib granules provide a bioequivalent alternative to tablets for patients prescribed a 50-mg dose and have difficulty swallowing tablets, an important consideration for convenience and compliance of this standard-of-care chronic therapy for patients with PROS. This study was registered in ClinicalTrials.gov on January 4, 2022 (NCT05195892).